Blood Pressure Nomograms for Children and Adolescents by Age and Body Mass Index in Tehran, Iran

Background: Normal standard references of blood pressure (BP) for children and adolescents should be constructed according to anthropometric indices. Therefore, we aimed to produce BP reference percentiles by body mass index (BMI). Methods: Data on demographic characteristics, anthropometric indices and BP values of 16246 3–18-year-old children and adolescents from 3 cross-sectional studies conducted in Tehran were included. To justify the need for BMI adjustment, quantile regression model was applied for different percentiles of systolic and diastolic BPs with age, sex, and the corresponding BMI percentiles. Then, Age- and sex-specific BP nomograms were constructed according to BMI. Results: All regression coefficients for BMI percentiles were significant in quantile regression of BPs, confirming the necessity for BMI-adjusted nomograms of BP. The BP percentiles for each gender by age and BMI are presented. All the BP percentiles rose steadily in all BMI percentiles with minor discrepancies between the two genders. As observed, the prevalence of hypertension is estimated to be lower among the lean subjects and higher among overweighs when the BMI-adjusted BP curves are considered. Conclusion: The reference database constructed in this survey is the first Iranian BP reference by age and BMI in children and adolescents, from it concluded that BMI-adjusted BP curves depict a more precise picture of the hypertension prevalence and present a more reliable classification standard for hypertension.


Introduction
Hypertension as a major cause of disability and premature deaths all around the world (13.5% of the premature deaths and 6% of the total global DALYs) is one of the most common risk factors for cardiovascular diseases and an important part of the worldwide burden of disease is attributable to high blood pressure (BP) (1). Hereon, major attention has been drawn to hypertension in adults and children and it has become a priority for the health policy makers to manage. Since early detection of hypertension is of utmost importance to help reduce its various complications, blood pressure assessment is now considered as an essential part of routine physical examination (2). Cardiovascular accidents most frequently happen after the age of fifty but evidence on pathophysiologic and epidemiologic aspects of the disease is available suggesting that hypertension and risk factors for cardiovascular disease originate in childhood (3). Some studies have also found a strong correlation between increased blood pressure levels in childhood and hypertension in adulthood (4)(5)(6). Considering the undeniable importance of primary prevention, many researchers have shown interest in evaluation of blood pressure trends in childhood and adolescence. Moreover, BP variations have been observed among different ethnicities and races (7)(8)(9)(10), therefore, standard nomograms derived from a specific population might not be suitable for others and local reference data should be considered instead (9)(10)(11)(12)(13)(14). In this regard, the United States' Task Force on BP Control in Children presented an extended series on age-and height-related BP values from birth to 18 yr to establish reference data for BP in children and adolescents (15)(16)(17). Many other countries have also presented similar reference data (7,8,10,18,19). Although few studies have presented references for systolic and diastolic BP measurements in Iranian population of children and adolescents (13,(20)(21)(22), only one study, was nationally representative and included the entire age groups of children and adolescents (23). In their survey they only presented the BP percentiles by age and height but since many studies have confirmed the stronger relation of BP with BMI (24-26), we aimed to construct BP percentiles by this factor for children and adolescents. To the extent of our knowledge, this is the first study looking at the BMI-related age-specific BP reference values in children and adolescents worldwide.

Study Population
Our study population included 16246 children and adolescents from Tehran, which as the capi-tal city of Iran, was proven to have a nationally representative population for the entire country (27). Subjects from three cross-sectional studies were included to constitute our study population of children and adolescents aged 3 to 18 yr old. All the three studies were conducted on randomized samples from 20 different geographical areas of Tehran. The first survey was conducted during Nov 2000 to Nov 2002 and included 8848 7 to 12-year-old primary school children from Tehran. The second one, conducted in 2004, included 6017, 12 to 18-year-old children and adolescents from secondary and high schools of Tehran. In the last survey, conducted in 2010, a 2stage cluster sampling method was used to select 2107 subjects including 1 month to 2-year-old infants from health centers and 2 to 7-year-old children from kindergartens (28). Being a healthy child, as the inclusion criterion was defined as 1) having a normal general appearance; 2) no documented underlying disease; 3) no history of cardiovascular problems; 4) no history of antihypertensive drugs. Trained interns of the medical center were responsible for data collection. Informed consent was obtained from the parents or guardians of the subjects. Our sampling methods are further explained in our previous publications (13,28,29).

Blood pressure measurements
A standard mercury sphygmomanometer (Model 1002/ Presameter, Riester, Germany) was used to measure BPs of all the children in a wakeful state after at least a 5-min rest, in a comfortable sitting position. The proper cuff was selected with a bladder long enough to cover 80%-100% of the arm circumference and width of approximately 40% the arm length. The right arm was positioned at heart level with the cuff placed around the arm leaving the antecubital fossa free for auscultation. While checking the radial pulse, the bladder was inflated to a level that occludes the artery and stops the pulse. With the stethoscope placed over the brachial artery in the antecubital fossa, the cuff was deflated. The pressure at which, the first Korotkoff (K1) sound was heard, was recorded as the systolic BP. For children under 12 yr old, the pressure at the onset of the K4 sound, and for adolescents aged 13 to 18 yr the pressure at the onset of the K5 sound was considered as the standards for diastolic BPs. BP was measured twice for each subject with an interval of 30 sec and the mean of the two values was recorded for data analysis.

Height and weight measurements
Children aged 3 to 6 yr old were weighed using a SECA scale (USA, model 760) with an accuracy of 500 gr and their standing height with an accuracy of 1 mm was measured by a SECA mechanical measuring tape (USA, model 206). For school-aged children height was measured with the student standing upright, barefoot, with the heels and back against a vertical SECA stadiometer (Germany, model 207). Weight without shoes and heavy outer clothing was measured via a daily-calibrated SECA balanced scale (Germany, model 710).

Body Mass Index (BMI)
Body mass (kg) divided by the square of the subject's height (m) was recorded as BMI.

Age-sex-specific percentile values
In order to evaluate the relationships between BMI with blood pressure measurements and age, first the age-sex-specific normal deviations (Z α ) of BMI were calculated (30). Then, the age-sexspecific percentile values of BMI were derived through mounting the computed Z α in the standard normal distribution and calculating the corresponding percentile value.

Construction of the BP nomograms according to age, sex and BMI
Two separate models were constructed for SBP and DBP of each gender to present BP percentiles as a function of age and BMI. At first, the latent moderated structural (LMS) equations method was applied to model BMI percentiles with age for males and females (31). Then the refer-ence curves for children and adolescents were fitted by age and BMI simultaneously. The Generalized Additive Models for Location Scale and Shape (GAMLSS) with the Box-Cox-Cole-Green distribution family (32)(33)(34) were fitted with GAMLSS 4.2-0 in the free statistical software R 2.15.2 (http://www.R-project.org) (23). Finally, we compared the fitted percentile curves with the reference values of USA (15), Germany (19), Turkey (10), Great Britain (8), China (18) and Saudi Arabia (7).

Results
Blood pressures, height, and weight of 8381 boys and 7865 girls aged 3-18 yr were measured. Table  1 demonstrates the baseline characteristics of the study population. As can be seen, the means of weight, height, and BMI in all the age groups were higher among boys compared to girls. As mentioned, BP was measured twice for each subject. The differences between the two measurements were insignificant. The means of absolute differences for boys and girls ranged 0.22-1.48 mmHg and 0.3-1.58 mmHg, respectively. Therefore, the mean of the two measurements was computed and used for the analysis. The mean of diastolic and systolic BPs is almost higher among boys for all the age groups, except for the SBP in age group of 7-12 yr where girls have a slightly higher mean. To justify the need for BMI adjustment, quantile regression model was performed for different percentiles of systolic and diastolic blood pressures with age, sex, and corresponding BMI percentile values. As illustrated in Table 2, all coefficients for BMI percentiles are statistically significant at P<0.001, confirming the necessity for BMI-adjusted nomograms of blood pressure. BP percentiles for boys and girls according to age and BMI are presented in Tables 3 and 4. No additional tables are required to interpret the presented information since the 5 th , 10 th , 25 th , 50 th , 85 th , 90 th and 95 th percentiles of BMI are given in kg/m 2 .  As can be seen, the 85 th percentile of BMI is given and the corresponding BPs are modeled because the 85 th to 95 th percentiles of BMI are defined as overweight. SBP values were mostly higher among the boys except for the ages of 9 through 13 where the curves nearly overlap. The DBP curves are somewhat different. The values of DBP before the age of 8 are higher among boys, but at this age, the curves cross and the DBP values for girls remain higher through the age of 18. Overall, the differences are milder than the SBP curves.
One of the benefits of constructing standard curves of BP by anthropometric indices is that the prevalence of hypertension can be better elucidated. Therefore, next in this article, we focused our assessments on estimating the prevalence of hypertension according to BMI since it is a better indicator of the subjects' nutritional status and it includes the effects of weight and height as well. The prevalence of hypertension using the US references presented in the fourth task force report for subjects whose BMI were in the <25th, 25th-85th, and >85th percentiles were 7.25, 7.72, and 8.10% for girls and 9.15, 5.24, and 6.92% for boys, respectively. However, when the BMI-adjusted BP percentiles were used, the prevalence of hypertension for the aforementioned BMI percentiles was 3.89, 7.46, and 13.33% for girls and 3.29, 3.93, and 10.03% for boys, correspondingly. As can be seen, when the BMIadjusted standard curves of BPs are used, the prevalence of hypertension is estimated to be lower among the lean subjects and higher among the over weights. Therefore, adjustment of these curves according to BMI decreases the false positive cases in lean subjects and false negative cases among overweight children and adolescents.

Discussion
The high prevalence of hypertension and its various complications associated with high morbidity and mortality rates, make it a major public health problem all around the globe (29). Since childhood BP levels are predictive of BP levels in adulthood, was provided normal standard refer-ences of BP for children and adolescents according to age, sex, and anthropometric indices (16,18,35). The American Academy of Pediatrics Task Force on Blood Pressure published a series of reports on BP levels according to age and height from birth to 18 yr to establish standard references for pediatric BP (15,36,37). Advanced statistical methods was applied on the data gathered through the German Health Interview and Examination Survey for Children (38) and Adolescents (KiGGS 2003-2006) (39) and presented standard BP references for nonoverweight, 3 to 17-year-old children and adolescents of Germany. The reference database constructed in this survey is the first BP reference by age and BMI in children and adolescents worldwide. In other studies, the standard curves of BP were only presented by age and gender. For example 5599 Turkish children from birth to 18 yr of age were evaluated (10). These researchers drew normal BP curves for Turkish pediatric population based on the collected data. BP centiles derived were presented from data gathered through examination of 22901 children aged 4 to 23 yr old from Great Britain (8). A similar survey was conducted in their country, Saudi Arabia (7). They constructed BP standard reference percentiles from data gathered from 16226 infants, children, and adolescents from birth to 18 yr of age. From China, (18) a study based on eleven large-scale were conducted cross-sectional BP surveys in their country included 112227 children and adolescents aged 3 to 18 yr old. We derived the analogous data on children and adolescents aged 3 to 18 from these surveys. For the information to be comparable with each other, only data on the 50 th percentile of height from the German references and the 50 th percentile of BMI from ours were included. Fig. 1 depicts the 95 th percentile of the BP values by age, for all the 7 surveys conducted on this matter. The SBP rose progressively with age in both genders, with the rise being steeper among boys after the age of 13. The DBP curves show slight differences between the two genders.  When the standard curves of BP were constructed according to BMI, the prevalence of hypertension increased among the overweight subjects and decreased in the lean population, preventing misinterpretations of the BP measurements.
Major strengths of our survey include the large and nationally representative sample, covering a wide range of ages, standardized measurements of BP, weight, and height, application of a BP measuring device validated in children, measuring BPs twice for each subject and the modeling by age and BMI simultaneously with advanced statistical methods. Measurements having been performed by human, imposed end-digit preference on our data, i.e. some values happened to be more frequently reported such as those ending in 0 or 5 (40). It does not meet the goodness of fit criteria and changes the fitted models along with the prevalence of hypertension calculated upon these fitted curves (41).

Conclusion
The reference curves constructed in this study is the first Iranian BP reference by age, and BMI, covering children and adolescents aged 3 to 18 yr old. BMI-adjusted BP curves depict a precise picture of the hypertension prevalence in children and adolescents and present a reliable meticulous classification standard for hypertension.

Ethical considerations
Ethical issues (Including plagiarism, informed consent, misconduct, data fabrication and/or falsification, double publication and/or submission, redundancy, etc.) have been completely observed by the authors.